EP2185543B1 - Procede de dedoublement optique de sels de l'omeprazole - Google Patents

Procede de dedoublement optique de sels de l'omeprazole Download PDF

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EP2185543B1
EP2185543B1 EP08828432.8A EP08828432A EP2185543B1 EP 2185543 B1 EP2185543 B1 EP 2185543B1 EP 08828432 A EP08828432 A EP 08828432A EP 2185543 B1 EP2185543 B1 EP 2185543B1
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solvate
omeprazole
enantiomer
racemic
mixture
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EP2185543A2 (fr
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Gérard Coquerel
Guillaume Tauvel
Marie-Noelle Petit
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Universite de Rouen
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Universite de Rouen
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention relates to the domain of the resolution of chiral compounds existing in the form of two optical antipodes (enantiomers), such as Omeprazole.
  • the invention makes it possible, from the racemic mixture, to separate the pure enantiomer (S) (-) omeprazole (Esomeprazole), of chemical nomenclature 5-methoxy-2 - [(S) - [4-methoxy-3,5] dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole and its pharmaceutically acceptable alkali salts.
  • the present invention relates to the resolution of potassium salts of racemic omeprazole by preferential crystallization and in particular by the AS3PC method (preferential polythermic crystallization programmed and self-seeded).
  • Racemic omeprazole is represented by the general formula (I) below:
  • the invention relates both to the omeprazole of formula (I) above and its tautomeric form, as well as to its salts and enantiomers hereinafter.
  • the magnesium salt of the (S) enantiomer of Omeprazole is the first proton pump inhibitor (PPI) developed and marketed as a pure enantiomer.
  • Racemic Omeprazole and Esomeprazole are used as gastric and / or duodenal anti-ulcer. They can be used in the prevention and treatment of gastrointestinal disorders, gastroesophageal reflux disease, gastrointestinal bleeding and dyspepsia.
  • (S) Omeprazole may be useful in the treatment of psoriasis and in the treatment of Helicobacter pylori infections and related diseases.
  • Omeprazole and its enantiomers belong to the chemical class of prazoles comprising a benzimidazole or imidazopyridine ring.
  • aprazole a benzimidazole or imidazopyridine ring.
  • prazoles and, more particularly, their corresponding alkaline or alkaline-earth salts are used as inhibitors of acidic gastric secretion and as such in treatments.
  • They are chiral sulphoxides whose sulfur atom bonded, on the one hand, to an oxygen atom and, on the other hand, to different heteroaromatic rings A and methylene-heteroaromatic ring substituents B, constitutes the stereogenic center.
  • Omeprazole (racemic compound) has been described for the first time in the patent EP 0 005129 and some of its alkali salts in patents EP 124495 and US 4,738,974 .
  • the alkaline and alkaline-earth salts and more particularly the magnesium salt of Omeprazole, and those of other prazoles IPP, have shown to be stable and for some of them non-hygroscopic.
  • Patent applications DE 40 35 455 and WO 94/27988 describe the resolution of racemic omeprazole and similar pyridinylmethylsulfinyl-1H-benzimidazole prazoles by fractional crystallization of diastereomeric salts and / or reverse phase chromatographic separation of covalent diastereomeric ethers of the type N-acyloxymethyl chiral bound to the free N atom of the benzimidazole ring, followed by basic hydrolysis.
  • the patent application WO 96/17077 describes a stereoselective bioreduction process of sulfoxide (racemic Omeprazole) to sulfide (thio-ether) corresponding to microorganisms such as Escherichia coli, Proteus mirabilis or Proteus vulgaris, containing the enzyme DMSO reductase or using of this purified enzyme.
  • This enantioselective bioreduction leaves the strongly enriched omeprazole enantiomer (+) with an enantiomeric excess 99% ee.
  • the enantiomer (-) is obtained with 70% ee.
  • the patent application WO 96/17076 describes a stereoselective biooxidation process of the sulphide (thioether), precursor of Omeprazole, in the presence of microorganisms such as Penicillium frequentans, Brevibacterium paraffinolyticum or Mycobacterium sp., to give the (S) omeprazole enantiomer of 99% ee.
  • the patent application WO 96/02535 describes the asymmetric synthesis involving the asymmetric oxidation of pro-chiral sulphide using the catalytic system, Ti (O-isoPr) 4 / di-ethyl-D-tartrate / H 2 O in the presence of cumene hydroperoxide of tertiary amine organic base and organic solvent such as toluene, followed by in situ formation of corresponding sodium salts.
  • This catalytic process makes it possible to obtain chiral sulphoxides, in particular the sodium salt of (S) Omeprazole of 99% ee.
  • the patent application WO 2006/040635 describes the enantioselective synthesis of pyridinylmethylsulfinylbenzimidazoles by catalytic oxidation of prochiral sulfide derivatives, corresponding precursors, using the same catalytic system, Ti (O-isoPr) 4 / di-ethyl-D-tartrate / H 2 O, cumene hydroperoxide, tertiary amine organic base without addition of organic solvent to give the enantiomer (S) Omeprazole and its alkali and alkaline earth salts, especially magnesium.
  • the patent application WO 03/089408 describes the asymmetric synthesis of (S) Omeprazole by catalytic enantioselective oxidation of precursor pro-chiral sulfide using a monodentate L-mandelic acid methyl ester chiral ligand in the presence of cumene hydroperoxide, Ti (O-isoPr) 4 / H 2 O and in situ preparation of the corresponding sodium salt of 99% ee.
  • the patent application WO 2004/002982 describes the separation of racemic Omeprazole into its pure enantiomers by formation of diastereomeric salts from the sodium salt of racemic Omeprazole in the presence of the diethyl-D-Tartrate / Ti coordinating agent (iso-Pr) 4 in acetone and complexation using L-mandelic acid.
  • the present invention is specifically intended to provide a method for preparing the pure enantiomer (S) Omeprazole which does not have the disadvantages described above.
  • the invention relates particularly to the application to potassium salts of racemic Omeprazole, resolution by preferential crystallization in each of its enantiomers, to obtain the (S) Omeprazole eutomer in an enantiomerically and chemically pure.
  • the preferential crystallization process AS3PC has been the subject of a completely original development excluding the constraining use of crystallization seeds.
  • This process is described for example in the following patents and patent applications FR 2,710,337 , WO 95/08522 , EP 0 720 595 and US 6,022,409 and in " G. Coquerel, Preferential Crystallization in Topical Current Chemistry, Novel Optical Resolution Technology, Springer, Berlin-Hei delberg, Eds K. Sakai, N. Hirayama and R. Tamura, 2007, 269, 1-51 .
  • AS3PC Auto-Seeded Programmed Polythermic Preferential Crystallization.
  • the preferred crystallization processes are based on the alternating crystallization of the two enantiomers (R) and (S), of the same racemic chemical species crystallizing in the form of conglomerate, in a medium that can be a solvent or a mixture of solvents or a set of constituents including the solvent (s) for a given temperature range ⁇ T.
  • this racemic mixture in thermodynamic equilibrium with its saturated solution, consists of two types of crystals each containing only molecules of the same absolute configuration.
  • Each enantiomer can incorporate solvent molecules (solvates) and / or water (hydrates).
  • racemic Omeprazole is not a conglomerate. This means that the preferred AS3PC crystallization method or any other preferred crystallization method can not be applied. It is the same for the sodium and magnesium salts.
  • the Applicant has found that the potassium salts of racemic omeprazole in the form of ethanol or ethylene glycol solvates are conglomerates without detectable solid solution.
  • the possible range of solid-state miscibility would be less than 1%, as shown in FIG. figure 1 .
  • the potassium salts of racemic omeprazole, a mixture enriched with enantiomer (S) of omeprazole or the pure enantiomer (S) omeprazole are stable in the presence of an excess of potassium hydroxide in alcohol-alcohol, alcohol-water or pure alcohol solvent mixtures. Under these conditions, concentration and temperature, these potassium salts have a non-congruent solubility (G. Coquerel in " Preferential Crystallization, in Topic in Current Chemistry, Novel Optical Resolution Technologies, Springer, Berlin-Heidelberg, Eds K. Sakai, N. Hirayama and R. Tamura, 2007, 269, 1-51 ). This means that in order to quantitatively obtain this enantiomeric excess salt greater than 99%, it is necessary to work in an alcoholic medium with an excess of potassium hydroxide.
  • the invention relates to a method for resolving racemic omeprazole, characterized in that the racemic omeprazole is converted into its potassium salt in the form of a solvate, in the presence of an excess of mineral base source of potassium, said potassium salt of the racemic omeprazole in the form of solvate being in the form of conglomerates whose partial solid solution domains, if they exist, are less than 1%, and then that is doubled said conglomerates by preferential crystallization to separate the two enantiomers (S) and (R) of said potassium salt of omeprazole.
  • the solvate of the potassium salt of the racemic omeprazole is selected from ethanol solvate or ethylene glycol solvate or a mixture thereof.
  • the resolution of the conglomerates according to the invention is carried out by preferential crystallization seeded or self-seeded.
  • the medium consists of an alcoholic solvent or mixture of alcoholic solvents, water and an excess of potassium hydroxide.
  • the medium consists of an alcoholic solvent or mixture of alcoholic solvents, water and an excess of potassium hydroxide.
  • the process of the invention in its various forms of implementation is simple, economical and easy; it does not require the use of chiral intermediates of organic, organometallic and / or resolving agents used in the form of salts or covalent diastereomers or appropriate microorganisms.
  • the solvent or mixture of solvents is of alcoholic type and preferably selected from ethanol, ethylene glycol, pure or in the presence of water with an excess of potassium hydroxide.
  • the racemic mixture, an equimolar mixture of enantiomers, in the medium used is for the temperature range T B -T F or T HOMO -T F , a conglomerate.
  • the mixture to be split is stable in this medium and in the temperature range used between T B and T F or T HOMO -T F.
  • the temperature T L corresponds to the dissolution temperature of the racemic mixture alone
  • the temperature T HOMO corresponds to the homogenization temperature of the solution enriched in one of the enantiomers
  • the temperature T I corresponds to the initial temperature of the seeded preferential crystallization process such that T I > T HOMO
  • the temperature T B corresponds to the initial temperature of the preferential crystallization process AS3PC such that T L ⁇ T B ⁇ T HOMO .
  • Knowledge of the supersaturation capabilities of the solutions between T L and T F is also useful, depending on the cooling kinetics.
  • the time of appearance of the crystals by primary nucleation in the racemic solution L (cf. figures 1 , 2 , 2a and 3 ) homogeneous, cooled from a temperature slightly higher than T L with the same kinetics, gives an indication of the supersaturation capacity tolerated by the conglomerate under these experimental conditions.
  • XRPD X-ray powder diffraction
  • the preferential crystallization split was systematically studied in ethanol and in ethanol / water and ethanol / ethylene glycol mixtures using the AS3PC method as recalled above and described in detail in WO 95/08522 . It was also studied in the azeotropic ethanol / water mixture using the inoculated process.
  • Table I shows the position and the relative intensity of the characteristic peaks for the ethanol solvate of the potassium salt of the racemic omeprazole and for the ethanol solvate of the enantiomerically pure (S) Omeprazole potassium salt. .
  • Table II shows the position and the relative intensity of the characteristic peaks for the ethylene glycol solvate of the potassium salt of racemic omeprazole and for the ethylene glycol solvate of the potassium salt of (S) enantiomerically pure Omeprazole. .
  • the racemic omeprazole thus obtained can then be subjected to preferential crystallization as described above.
  • the operations are carried out alternately in two ground-neck tubes (29/32), except at the scale of 2 liters, that is to say for examples 5 and 6.
  • These tubes measure 19 cm in height and 45 mm diameter for Examples 1, 2, 3, 4 and 7, and about 12 cm in height and 29 mm in diameter for Example 8.
  • These tubes are provided, in their upper part, with a lateral tube to establish a depression necessary for filtration.
  • the crystals are recovered on sintered glass No. 2 or 3, or on Buchner, adaptable on each tube by means of a rubber ring. Stirring is provided by a magnetic bar. Mother liquor passes successively from one tube to another.
  • the compensation process is refined. A small amount of the solution is taken in order to determine the composition, allowing a rigorous compensation.
  • the coolant circulating in the double jacket of each crystallization chamber is regulated in temperature with an accuracy of ⁇ 0.1 ° C.
  • the apparatus used makes it possible to fix a law reproducible cooling.
  • These crystallization chambers are thermostatically controlled using a thermostat (LAUDA RE107) fitted with a jacket with a double jacket.
  • Example 5 the operations are carried out in a 2-liter jacketed reactor thermostatically controlled by a thermostat (Huber CC 415) and equipped with a bottom valve.
  • the agitation is mechanical and is provided by means of a double helix blade.
  • the filtration is carried out by means of a wringer (RA20 Rousselet-Robatel) at 5000 rpm with a sock of 20 cm in diameter, 10 cm in height and whose pore diameter of the nylon filter media is 20 ⁇ m.
  • the recovered mother liquor is transferred to the reactor for the next preferential crystallization.
  • Example 1 Duplication in the azeotropic ethanol / water mixture by preferential crystallization seeded
  • Example 2 Duplication in the azeotropic ethanol / water mixture by preferential self-priming crystallization
  • Example 3 Duplication in the azeotropic ethanol / water mixture by preferential self-priming crystallization
  • Example 4 Duplication in an ethanol / water mixture by crystallization preferential self-seeded
  • the ethanol / water mixture is estimated at 86/14% w / w.
  • Example 5 Duplication in an ethanol / water mixture (90/10% w / w) by preferential self-priming crystallization at the 2-liter scale
  • Solubility of the racemic mixture in the ethanol / water mixture (90/10% w / w) containing 1.2 molar equivalents of potassium hydroxide (ie an excess of potash of 0.2 equivalents): Coordinates of point L : 25% by mass; temperature T L : 30 ° C Temperature (° C) 30 Solubility (% by mass) 25
  • Example 6 Duplication in a ethanol / water mixture (93/7% w / w) by preferential self-priming crystallization at the 2-liter scale
  • Example 7 Duplication in ethanol by preferential self-priming crystallization
  • Example 8 Duplication in the ethanol / ethylene glycol mixture (80/20% w / w) by preferential self-priming crystallization
  • the pure enantiomer corresponds to a mixture between the ethanol solvate of the potassium salt of (S) Omeprazole and the ethylene glycol solvate of the potassium salt of (S) Omeprazole
  • a single crystal was obtained in a saturated solution of racemic Omeprazole prepared by dissolving the racemic omeprazole in an ethanolic potassium hydroxide solution. Nucleation and then growth of the single crystal were induced by decreasing the temperature causing the supersaturation of the salt solution.
  • the crystal structure of the single crystal has been solved in the monoclinic system, space group P2 1 .
  • the elemental crystal mesh contains an anionic molecule of omeprazole, a potassium cation and two ethanol molecules.
  • the diffraction intensities were measured with an automated SMART APEX diffractometer (BRUKER) with SMART software (SMART for WNT / 2000 V5.622 (2001), Smart software reference manual, Bruker Advanced Ray Solutions, Inc., Madison, Wisconsin). , USA) and the structure was solved with the software SAINT +, SADABS and SHELXS (SAINT + V6.02 (1999), Saint software reference manual, Bruker Advanced Ray Solutions X, Inc., Madison, Wisconsin, USA).
  • the reliability factor R1 is 3.09%, which indicates that the resolution is satisfactory.
  • the value of the Flack parameter is 0.11, which makes it possible to conclude that the molecule, in the studied crystal, is indeed of absolute configuration (S).
  • Table V Identification Potassium salt of (S) Omeprazole solvated with 2 ethanol molecules Chemical formula C 21 H 30 KN 3 O 5 S 1 Molar mass ( g.mol - 1 ) 475.64 Crystal system monoclinic Space group P2 1 Z, Z ' 2, 1 a ( ⁇ ) 11,057 b ( ⁇ ) 7.708 c ( ⁇ ) 13989 ⁇ (°) 90.0 ⁇ (°) 100.12 ⁇ (°) 90.0 V ( ⁇ 3 ) 1173.8
  • the 3D representation of the crystalline mesh, built using the DIAMOND software, presented on the figure 6 reveals the benzimidazole anion, the potassium cation and 2 molecules of ethanol. There is no direct electrostatic bond between the nitrogen atoms of the benzimidazole ring and the K + cation. The link is made via the relay of an ethanol molecule.
  • Table VI Atomic coordinates (x10 ⁇ 4) and isotropic displacement parameters (A ⁇ 2 x 10 ⁇ 3).
  • x there z U (eq) K (1) 10723 (1) 7414 (1) 10034 (1) 40 (1) S (1) 7268 (1) 6353 (1) 10330 (1) 32 (1) N (1) 9493 (2) 9468 (2) 11377 (1) 37 (1) O (4) 13316 (1) 7340 (3) 10314 (1) 48 (1) C (8) 5798 (2) 7542 (3) 7719 (1) 36 (1) N (3) 6824 (1) 7257 (3) 8417 (1) 38 (1) O (5) 9024 (2) 9070 (3) 8606 (1) 55 (1) C (10) 8449 (2) 8839 (2) 11601 (1) 32 (1) O (1) 9268 (2) 8297 (3) 14226 (1) 62 (1) C (16) 8317 (2) 8429 (3) 12556 (1) 37 (1) C (17) 7142 (2) 7704 (4) 12789 (2) 53 (1) N (2) 5106 (1) 6797 (2) 9104 (1) 38 (1) C (2) 47
  • the temperature is gradually lowered until the rotatory power of the mother liquor is close to zero.
  • the solid obtained is filtered on Buchner. After drying, the mass of the potassium salt recovered is 7.7 g (for 8.16 g theoretically recoverable), ie a yield greater than 94%, with an enantiomeric purity greater than 99% ee (measured by chiral HPLC chromatography).
  • the temperature is brought to 50 ° C for half an hour then is brought to 30 ° C quickly and up to 14 ° C slowly by polarimetrically monitoring the evolution of the rotating power of the mother liquor.
  • the temperature is raised to 16 ° C for 12 hours in order to reach the thermodynamic equilibrium in the two-phase domain (enantiomer (-) of the diethanolate of the potassium salt of Omeprazole and its saturated solution). Once at equilibrium, the temperature is lowered to 13 ° C to have a driving effect and recover a higher enantiomer mass.
  • the filtration takes place on a wringer (RA20 Rousselet-Robatel France) at 5000 rpm with a sock 200 mm in diameter, 100 mm high and whose pore diameter of the nylon filter medium is 20 ⁇ m. .
  • a wringer RA20 Rousselet-Robatel France
  • the collected mass is 352g.
  • HPLC analysis was performed to measure the optical purity of the sample after recrystallization.
  • the purity is 99.4% ee and the yield is 95%.
  • the racemic omeprazole (1.01 g) is dissolved in a mixture of methanol and ethylene glycol (respectively 4 mL and 1 mL) in the presence of potassium hydroxide (180 mg, 1.1 molar equivalents). After stirring for 3 hours at room temperature, the solid is recovered by filtration on Buchner. The solid obtained corresponds to a mixture of phases between the methanol solvate and the ethylene glycol solvate of the potassium salt of Omeprazole racemic. After drying, the methanol solvate becomes amorphous, the only phase observed by X-ray diffraction on powder is the ethylene glycol solvate. The diffractogram (XRPD) is presented on the figure 5 .
  • XRPD diffractogram
  • the diffractogram (XRPD) is presented on the figure 5 .

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EP08828432.8A 2007-08-29 2008-08-29 Procede de dedoublement optique de sels de l'omeprazole Active EP2185543B1 (fr)

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SI200831258T SI2185543T1 (sl) 2007-08-29 2008-08-29 Postopek za optiäśno loäśevanje soli omeprazola

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FR0706058A FR2920428B1 (fr) 2007-08-29 2007-08-29 Procede de dedoublement de sels de l'omeprazole
PCT/FR2008/051547 WO2009027614A2 (fr) 2007-08-29 2008-08-29 Procede de dedoublement de sels de l'omeprazole

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FR2909380B1 (fr) * 2006-12-04 2009-02-20 Sidem Pharma Sa Sa Conglomerats de sels de potassium de tenatoprazole
WO2010097583A1 (en) * 2009-02-24 2010-09-02 Cipla Limited Esomeprazole potassium polymorph and its preparation
CA2770338A1 (en) * 2009-08-27 2011-03-03 Merck Sharp & Dohme Corp. Processes for preparing protease inhibitors of hepatitis c virus
FR2954310B1 (fr) 2009-12-18 2014-07-25 Univ Rouen Procede de dedoublement d'enantiomeres par evapocristallisation preferentielle
FR2959509B1 (fr) 2010-05-03 2012-07-13 Prod Chim Auxiliaires Et De Synthese Phase precurseur et son utilisation pour preparer le sel de magnesium tetrahydrate d'un enantiomere d'omeprazole
CN102993184A (zh) * 2013-01-08 2013-03-27 湖南方盛制药股份有限公司 一种埃索美拉唑及其镁盐三水合物的制备方法
CN103524491A (zh) * 2013-10-16 2014-01-22 江南大学 埃索美拉唑镁盐四水合物的三种晶型及其制备方法
NZ714742A (en) * 2014-04-16 2017-04-28 Signal Pharm Llc Solid forms of 1-ethyl-7-(2-methyl-6-(1h-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1h)-one, compositions thereof and methods of their use
CN104844572B (zh) * 2015-04-02 2017-06-20 天津大学 一种奥美拉唑钠1,2‑丙二醇溶剂化物及制备方法
FR3054218B1 (fr) * 2016-07-22 2020-03-06 Universite De Rouen Procede de dedoublement de sels de baclofene
IL271491B2 (en) 2017-06-22 2023-09-01 Celgene Corp Treatment of carcinoma of the liver characterized by hepatitis b virus infection

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FR2909380B1 (fr) * 2006-12-04 2009-02-20 Sidem Pharma Sa Sa Conglomerats de sels de potassium de tenatoprazole

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CN102131799B (zh) 2014-06-18
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JP2010540413A (ja) 2010-12-24
CN102131799A (zh) 2011-07-20
EP2185543A2 (fr) 2010-05-19
US8034948B2 (en) 2011-10-11
SI2185543T1 (sl) 2014-11-28
FR2920428A1 (fr) 2009-03-06
US20090124811A1 (en) 2009-05-14
WO2009027614A2 (fr) 2009-03-05
ES2493639T3 (es) 2014-09-12
CA2697724C (fr) 2017-03-14
WO2009027614A3 (fr) 2010-09-02
JP5656635B2 (ja) 2015-01-21
FR2920428B1 (fr) 2012-06-15

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